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Cancer Cell. 2019 Mar 18;35(3):473-488.e6. doi: 10.1016/j.ccell.2019.02.006.

CD40 Ligand-Modified Chimeric Antigen Receptor T Cells Enhance Antitumor Function by Eliciting an Endogenous Antitumor Response.

Author information

1
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: brentjer@mskcc.org.

Abstract

Chimeric antigen receptor (CAR) T cells provide great efficacy in B cell malignancies. However, improved CAR T cell therapies are still needed. Here, we engineered tumor-targeted CAR T cells to constitutively express the immune-stimulatory molecule CD40 ligand (CD40L) and explored efficacy in different mouse leukemia/lymphoma models. We observed that CD40L+ CAR T cells circumvent tumor immune escape via antigen loss through CD40/CD40L-mediated cytotoxicity and induction of a sustained, endogenous immune response. After adoptive cell transfer, the CD40L+ CAR T cells displayed superior antitumor efficacy, licensed antigen-presenting cells, enhanced recruitment of immune effectors, and mobilized endogenous tumor-recognizing T cells. These effects were absent in Cd40-/- mice and provide a rationale for the use of CD40L+ CAR T cells in cancer treatment.

KEYWORDS:

CAR T cells; CD40; CD40 ligand; antigen-presenting cells; chimeric antigen receptor; endogenous T cells; immunotherapy; leukemia; lymphoma

PMID:
30889381
PMCID:
PMC6428219
[Available on 2020-03-18]
DOI:
10.1016/j.ccell.2019.02.006

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